Field of the Invention
The disclosure provided herein relates to a genetically modified bovidae, specifically a goat, as a model for studying cardiac fibrosis and fibrosis associated cardiac pathologies in human-sized hearts. The disclosure provided further relates to methods by which genetically modified goats and other bovidae may be produced.
Description of the Related Art
Human and animal studies indicate that fibrosis plays a central role in the cardiac remodeling observed in various cardiac diseases. In fibrosis, profibrotic factors act on cardiac cells to increase the deposition of extracellular matrix (ECM). These changes alter the structure, architecture and shape of the heart to affect three aspects of cardiac function: electrical conduction, ventricular contractility and valvular function. Transforming growth factor β1 (TGF-β1) is involved in pathologies associated with each of these cardiac functions.
Small animal models, such as mouse, have been useful for cardiovascular research. However, due to the small heart size, functional electrophysiology of transgenic mice is problematic. Mouse models are also not suitable for advancing the development of implantable devices, ablation therapies, or improved imaging techniques. Mice that overexpress TGF-β1 have profound atrial fibrosis and increased susceptibility to induction of atrial fibrillation via rapid atrial pacing. Atrial fibrosis alters atrial excitability as well as electrical conduction.
Histological analysis of atrial biopsy samples from patients with lone atrial fibrillation (AF) (not caused by an underlying heart disease) showed that 75% of these individuals exhibited atrial fibrosis. Additionally, studies using several animal models found that chronic atrial fibrosis increases AF vulnerability. Furthermore, myocardial fibrosis reduces ventricular compliance, with a two to three-fold rise in collagen volume causing significant ventricular stiffening. Systolic dysfunction is also associated with increased myocardial collagen concentration. TGF-β1 expression is elevated in patients with dilated and hypertrophic cardiomyopathies as well as aortic stenosis and regurgitation. These findings indicate a pivotal role of TGF-β1 in a wide range of cardiac pathologies.